Method of preventing allograft rejection

Abstract

A method for suppressing the rejection of allogeneic transplants in a mammal, including a human, comprising administering to said mammal an effective amount of the compound of the formula wherein n, A, B, R1 and R2 are as defined above, or the pharmaceutically acceptable salt thereof.

What is claimed is: 
     
       1. A method for suppressing the rejection of allogeneic transplants in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of the formula ##STR7## or a pharmaceutically acceptable acid addition salt thereof; wherein n is 1, 2 or 3; A is oxygen, sulfur, CH 2 , NH or N(C 1  -C 6 )alkyl;   B is CR 4  R 5  wherein R 4  and Rs are each independently selected from hydrogen, (C 1  -C 6 )alkyl, R6R7(C 1  -C 6  alkyl or R 6  R 7  (C -Cjalkoxy wherein Re and R 1  are each independently hydrogen, (C 1  -C 6 )alkyl, (C 3  -C 9 )cycloalkyl, (C 6  -C 10 )aryl or (C 4  -C 6 )heteroaryl wherein the aryl and heteroaryl substituents are optionally substituted by one or two groups selected from fluoro, chloro, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, perfluoro(C 1  -Cjalkyl, perfluoro(C 1  -C 6 )alkoxy, (C 1  -C 6 )alkylthio, (C 1  -CJalkylsulfinyl, (C 6  -C 10 )arylsulfinyl, (C 1  -C 6 )alkylsulfonyl, (C 6  -Clo)arylsulfonyl or R 14  (C 8  -C 1  O)aryl wherein R 14  is fluoro, chloro, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, perfluoro(C 1  -C 6 )alkyl, perfluoro(C 1  -C 6 )alkoxy, (C 1  -C 6 )alkyfthio, (C 1  -C 6 )alkylsulfinyl or (C 1  -C 6 )alkylsulfonyl;   or R 4  and Rs may be taken together with the carbon to which they are both attached to form a (C 4  -C 7 )cycloalkyl group;   R 1  is tetrazolyl, carboxy, carboxy(C 2  -Cjalkenyl optionally substituted by one or two (C 1  -Cdalkyl groups; (C 1  -C 6 )alkyl, (C 3  -C 7 )cycloalkyl, (C 3  -C 6 )cycloalkyl(C 1  -Cjalkyl wherein the alkyl or cycloalkyl groups are optionally substituted by hydroxy, carboxy or tetrazolyl; or a group of the formula ##STR8## wherein a is 0, 1, 2, 3 or 4; R 8  and R 5  are each independently hydrogen or (C 1  -C 6 )alkyl; and   R 10  and R" 1  are each independently hydrogen, hydroxy, (C 1  -C 6 )alkyl, perfluoro(C 1  -C 6 )alkyl, (C 1  -CO)alkylsutfinyl, (C 6  -C 10 )aryisulfinyl, R 15  sulfonyl wherein Rl 5  is (C 1  -C 6 )alkyl, perfluoro(C 1  -C 6 )alkyl, (C 3  -C 8 )cycloalkyl, (C 6  -Clo)aryl or (C 4  -C 9 )heteroaryi;   or (C 6  -C 10 )aryI wherein each aryl or heteroaryl substituent is optionally substituted by one ortwo groups selected from fluoro, chloro, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, perfluoro(C 1  -C 6 )alkyl 1  perfluoro(C 1  -C 6 )alkoxy, (C 1  -C 6 )alkyflthio, (C 1  -C 6 )alkylsulfinyl, (C 1  -C 6 )alkyisuifonyl and (C 6  -C 10 )arylsulfonyl;   or a group of the formula ##STR9## wherein b is 0, 1, 2 or 3; c is 0 or 1;   Y is oxygen, sulfur, CH 2 , NH or N(C 1  -C 6 )alkyl; and   Z is (C 6  -C 10 )aryl or (C 4  -C 9 )heteroaryl wherein the aryl or heteroaryl substiuents are optionally substituted by one to three groups selected from fluoro, chloro, (C 1  -C 6 )alkyl optionally substituted by hydroxy; R 12  SO 2  NH wherein R 12  is (C 1  -C 6 )alkyl or perfluoro(C 1  -C 6 )alkyl; R 13  SO 2  NHCO wherein R 13  is (C 1  -CO)alkyi, (C 6  -C 10 )aryl or (C 4  - C9)heteroaryl wherein aryl or heteroaryl subtituents are optionally substituted by R 14 , (C 6  -C 10 )aryl or R 14  (C 6  -C 10 )aryl wherein R 14  Is as defined above; (R" 5  SO 2 )NH, (R5CO)NH, (R" CO 2 )NH wherein R 15  is as defined above; (C 1  -C 6 )alkoxy, perfluoro(C 1  -C 6 )alkyl, perfluoro(C 1  -C 6 )alkoxy, (C 1  -C 6 )alkylthio, (C 1  -C 8 )alkylsutfinyl, (C 1  -C 6 )alkylsulfonyl, carboxy, tetrazolyl or the group of formula 11 wherein a, RI, R 9 , R° and R 11  are as defined above; and   R 2  is hydrogen, fluoro, chloro, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, perfiuoro(C-C 6 )alkyl, perfluoro(C 1  -C 6 )alkoxy, (C 1  -C 6 )alkyfthlo, (C 1  -C 6 )alkylsuffinyl, (C 6  -Clo)arylsuffinyl, (C 1  -C 6 )alkylsuffonyl or (C 6  -C 10 )arylsulfonyl.   
     
     
       2. A method according to claim 1, wherein the compound that is administered Is one wherein n is 2. 
     
     
       3. A method according to claim 1, wherein the compound that is administered is one wherein A Is oxygen. 
     
     
       4. A method according to claim 1, wherein the compound that Is administered is one wherein n is 2 and B, in the 3-position, is CR 4  R 5  wherein R 1  is hydrogen and R 5  is benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4-fluorophenyl)benzyl or phenoxy. 
     
     
       5. A method according to claim 1, wherein the compound that Is administered is one wherein R 2  is hydrogen or fluoro. 
     
     
       6. A method according to claim 1, wherein the compound that is administered is one wherein n is 2 and RI, in the 7-position, is 2rboxyphenyl, 2- carboxylhlorophenyl,2-carboxychlorophenyl,2carboxyfiuorophenyl,2-carboxy- 5-fluorophenyl, 2-carboxy-5-chlorophenyl, 2rboxy-trifluoromethylphenyl, 2- trifluoromethylsuIfonylaminefluorophenyl, 2rboxy4fluorophenyl, 2rboxyS fluorophenyl, 2-tetrazoyl-5-fluorophenyl or 3-carboxyphenyl. 
     
     
       7. A method according to claim 1, wherein the compound that is administered is one wherein n is 2; A is oxygen; B, in the 3-position, is CR 4  FR wherein R4 is hydrogen and Rs is benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4- fluorophenyl)benzyl or phenoxy; R 2  is hydrogen or fluoro; and RI, in the 7-position, is 2 carboxyphenyl, 2caboxy-5chlorophenyl, 2wboxychlorophenyl, 2rboxyf fluorophenyl, 2-carboxy-5-fluorophenyl, 2-carboxy-5-trifluoromethylphenyl, 2- trlfluoromethylsuifonylamine-5-fluorophenyl, 2rboxy4fluorophenyl, 2rboxy6 fluorophenyl, 2-tetmzoyifiuorophenyl or 3rboxyphenyl. 
     
     
       8. A method according to claim 1, wherein said compound is selected from the group consisting of: (3S,4R)-7-(2rboxyphenyl)hydroxy3benzyl-2 H-1 benzopyran;   (3S,4R)-7-(2-carboxyschlorophenyl)hydroxyffibenzyi-2 H-1 -benzopyran;   (3S,4R)-7-(2carboxychlorophenyl)hydroxyfbenzyl-2 H-1 -benzopyran;   (3S,4R)-7-(2rboxy-fluorophenyl)4hydroxybenzyl-2 H-1 -benzopyran;   (3S,4R)-7-(2-carboxy44fluorophenyl)4hydroxy4benzyl-2 H-1 -benzopyran; (3S,4R)-7-(2rboxyuorophenyl) 4ydroxyfbenzyl-2 H-1-benzopyran;   (3S ,4R)-7-(2-carboxy-5-trifluoromethylphonyl)-4-hydroxy-3-benzyl-2 H-1 - benzopyran;   (3S,4R7q2-tffluoromethylsufonylamine5fluorophonyl)+hydroxyfbenzyl-2 H- 1 -benzopyran;   (3S,4R)-7-(2tetrazoyfluorophenyl) 4ydroxyenzyl-2 H-1-benzopyraniand (3S,4R)-7-(3-carboxyphenyl)4hydroxyfbenzyl-2 H-1 -benzopyran.